Project Summary/Abstract In patients with type 2 diabetes mellitus (T2DM), exercise elicits an excessive increase in blood pressure (BP). Since such an exaggerated BP response to physical exertion increases the risk for the development of an unfavorable cardiovascular event, elucidating the mechanisms responsible is clinically important. The exercise pressor reflex (EPR, a reflex originating in skeletal muscle) plays a pivotal role in regulating the cardiovascular system during exercise. Sensory signals from exercising muscle are generated by activation of mechanically sensitive (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) afferent neurons. Although it has been shown that muscle metaboreflex function is augmented in T2DM patients, it remains to be elucidated whether the muscle mechanoreflex is altered as well. Chronic hyperinsulinemia associated with peripheral insulin resistance is one of the pathophysiological characteristics of T2DM. Insulin directly influences the nociceptive ion channel function of the transient receptor potential vanilloid receptor 1 (TRPV1) in muscle known to contribute significantly to metaboreflex function, suggesting that hyperinsulinemia may peripherally augment EPR function in T2DM. In contrast, chronic hyperinsulinemia results in impairment of insulin transport to the central nervous system, decreasing the activity of the insulin signaling pathway in the brain. Thus, peripheral and central changes in insulin handling may contribute to the generation of abnormal EPR activity in T2DM. The global objective of this proposal is to determine the mechanisms underlying the heightened BP response to exercise in T2DM. We hypothesize that alterations in muscle mechanoreflex and metaboreflex function significantly contribute to the evolution of abnormal circulatory control in T2DM and that central as well as peripheral insulin resistance potentiates EPR activity in T2DM. We further hypothesize that the enhanced BP response to exercise in T2DM is ameliorated by blocking chemically sensitive muscle receptors peripherally or increasing the delivery of insulin centrally. Therefore, we propose in vivo and in vitro studies in diabetic animals to integratively determine: a) whether the heightened exercise BP in T2DM is mediated by an overactive muscle mechanoreflex as well as metaboreflex (specific aim 1); b) whether peripheral insulin resistance leading to muscle hyperinsulinemia contributes to the exaggerated EPR in T2DM which can be ameliorated by antagonizing TRPV1 and mechanically sensitive receptors (specific aim 2); and c) whether central insulin resistance leading to brain hypoinsulinemia contributes to the exaggerated EPR in T2DM which can be ameliorated by increasing central delivery of insulin (specific aim 3). The proposed studies are innovative in that they maintain the potential to shift current clinical practice paradigms by identifying insulin resistance as a key target for the prevention and treatment of abnormal cardiovascular control in diabetes. Ultimately, the results of our work could lead to more effective strategies for reducing the global burden of diabetes-associated cardiovascular disease.